Drug Interactions and the Statins

Drug interactions and the statins Robert J. Herman, MD Education Abstract Éducation DRUG INTERACTIONS COMMONLY OCCUR in patients receiving treatment with multiple medications. Most interactions remain unrecognized because drugs, in general, From the Department of have a wide margin of safety or because the extent of change in drug levels is small Pharmacology, College of when compared with the variation normally seen in clinical therapy. All drug inter- Medicine, University of actions have a pharmacokinetic or pharmacodynamic basis and are predictable Saskatchewan, Saskatoon, given an understanding of the pharmacology of the drugs involved. Drugs most li- Sask. able to pose problems are those having concentration-dependent toxicity within, or close to, the therapeutic range; those with steep dose–response curves; those hav- This article has been peer reviewed. ing high first-pass metabolism or those with a single, inhibitable route of elimina- CMAJ 1999;161(10):1281-6 tion. Knowing which drugs possess these intrinsic characteristics, together with a knowledge of hepatic P-450 metabolism and common enzyme-inducing and enzyme-inhibiting drugs, can greatly assist physicians in predicting interactions that may be clinically relevant. This article reviews the pharmacology of drug interactions that can occur with hydroxymethylglutaryl – coenzyme A (HMG–CoA) re- ductase inhibitors (statins) to illustrate the scope of the problem and the ways in which physicians may manage this important therapeutic class of drugs. Background All important drug interactions, with the possible exception of idiosyncratic or allergic reactions, have a pharmacokinetic or pharmacodynamic basis, or both.1,2 Pharmacokinetic interactions refer to those where drugs or other factors cause an alteration in the concentration of unbound drug acting on the tissues. They include interactions that may lead to changes in drug absorption, drug distribution (either through binding to plasma proteins or, more importantly, binding and uptake into tissues) and drug elimination. Pharmacodynamic interactions refer to those where changes occur in tissue sensitivity or response to the same unbound drug concentrations. The consequences of a drug interaction depend upon patient-related as well as drug-related factors (Fig. 1).3 These include the magnitude and direction of the concentration or effect changes, as well as the steepness and separation of the dose–response of the drug’s intended (therapeutic) and unintended (adverse) phar- macologic actions.1 Large changes in the concentration or tissue response to a drug possessing a flat dose–response relation or low intrinsic toxicity may be of little clinical importance. Alternatively, small changes in the concentration of potent or highly toxic drugs can be disastrous. Individual susceptibility to adverse drug effects because of health- (e.g., age, pregnancy) and disease-related factors (e.g., renal, hepatic, CNS) should also be considered. As well, the body may minimize a drug’s effect through offsetting changes in tissue sensitivity, by up-regulation or down-regulation of receptor numbers or by changes in receptor–effector coupling, or both.4 What might produce minimal impairment on one occasion could be incapacitating on another occasion or in a less tolerant individual. Interactions between drugs binding to the same sites on plasma proteins are rarely associated with changes in drug response.1,2 The reason for this is that most of the drug exists in the body in tissue stores, mainly in muscle and fat, not in the circulation. Thus, even large decreases in the amount of drug bound to plasma proteins is effectively buffered by a greater distribution in peripheral tissues with little or no change in unbound concentrations. The one exception occurs with drugs possessing CMAJ • NOV. 16, 1999; 161 (10) 1281 © 1999 Canadian Medical Association or its licensors Herman small distribution volumes, like warfarin, where binding in- pathways as long as they are unencumbered. Therefore, teractions confined largely to the circulation produce large drugs that have few or minor alternative pathways are par- changes in unbound concentrations and drug effects. What ticularly prone to large concentration increases when elimi- is important to remember is that laboratories usually report nation is impaired. total drug concentrations and not unbound drug concentra- First-pass metabolism by the gut and liver is another im- tions. Therefore, target ranges of clinically monitored drugs portant consideration. If a drug has low oral availability due should be adjusted downwards in the presence of a binding to high presystemic elimination, there may be large in- interaction, normally with no change in dosage. Similar creases in the amount of drug getting into the body if me- considerations apply if the levels of albumin or other bind- tabolism is inhibited. Where the parent drug is inactive and ing proteins are not within the expected range. the pathway normally results in the formation of an active In contrast, displacement from tissue-based binding sites metabolite, drug response may diminish rather than in- or the inhibition of carrier-mediated uptake into tissues can crease when metabolism is inhibited.9 Conversely, response produce large changes in unbound drug concentrations.2 may be unchanged if both parent and metabolites are active Drugs and their metabolites move out of tissues as readily — increases in the concentration of the parent offset by de- as they move in, and muscle and fat often contain large creases in the metabolites.9 body stores, particularly following multiple dosing. The The mechanism of interaction is also an important fac- factors causing redistribution from tissues into the circula- tor; an interacting drug may not be a known inhibitor but tion are not well understood, although evidence suggests merely a substrate for the same metabolic pathway and that this occurs commonly with lipophilic drugs that have thereby produce only minor dose-dependent competition large distribution volumes.5 Examples of clinically relevant at the active enzyme site.10 In this case, the affinity of the interactions involving the inhibition of drug distribution substrate for the enzyme and the unbound concentration and transport include the 2- to 3-fold elevations in digoxin and half-life of the inhibiting drug are important determi- serum concentrations following the concomitant adminis- nants of the extent and time course of the interaction. Al- tration of quinidine or verapamil.6 ternatively, inhibition may be noncompetitive or uncom- The inhibition or induction of hepatic drug metabolism petitive, wherein the effect is likely to be more complete is a major source of variability in drug response and is the and long lasting, requiring resynthesis of new enzyme be- basis of many adverse drug interactions.7 Paramount to an fore it can be overcome.10 understanding of this is a consideration of the role of the liver in the overall elimination of the drug. Most drugs are The cytochrome P450 superfamily removed from the body through multiple competing pathways of renal and hepatic excretion. If one or several of Hepatic metabolism is served by a superfamily of oxyge- these become blocked because of disease or the action of nases known as the cytochrome P450s. The purpose of another drug, clearance will diminish, dependent upon the these enzymes is to add a functional group to a drug, an en- relative contribution of the affected pathway(s) to the total vironmental chemical or an endogenous molecule and, in elimination of the drug.8 If this occurs, steady-state concen- so doing, increase either its polarity and excretion from the trations and, correspondingly, drug or adverse effects rise. body or its interaction with similar enzymes. The most dis- However, these in turn drive elimination through other tinguishing characteristic of the cytochrome P450 family is its great diversity; members have a broad and overlapping substrate specificity and an ability to interact with almost any chemical species. The superfamily, referred to as the CYP enzymes, is subdivided according to the degree of homology in amino acid sequences. CYP enzymes possessing more than 40% homology are grouped together into families, which are designated by an Arabic numeral (e.g., the CYP1 family). Families are further divided into subfamilies, which are designated by a letter after the number (e.g., CYP2C and CYP2D subfamilies); members of each subfamily have more than 55% homology with one another. Finally, individual members are given an additional number (e.g., CYP3A4) to identify a specific enzyme pathway. Over 70 CYP families have been identified to date, of which 14 are known to occur in all mammals.11 Of the 26 mammalian subfamilies, the CYP2C, CYP2D and CYP3A subfamilies are involved in the metabolism of most clinically relevant Fig. 1: Factors influencing drug interactions. (Adapted from drugs. Important substrates, inducers and inhibitors of the Hansten).3 major CYP enzymes are listed in Table 1. 1282 JAMC • 16 NOV. 1999; 161 (10) Drug interactions The CYP2C subfamily comprises about 20% of all of CYP2C isozymes have been characterized, each having the cytochrome P450s in the liver.12 At least 6 different greater than 80% homology with distinct but overlapping Table 1: Inducers and inhibitors of major CYP enzymes Enzyme; substrate Enzyme inducers Enzyme inhibitors CYP1A2 TCAs Omeprazole, lansoprazole Fluvoxamine (other SSRIs weak) Haloperidol,

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